CA2477773C - A stable diclofenac-tromethamine composition for the topical treatment of oropharyngeal cavity disorders - Google Patents
A stable diclofenac-tromethamine composition for the topical treatment of oropharyngeal cavity disorders Download PDFInfo
- Publication number
- CA2477773C CA2477773C CA2477773A CA2477773A CA2477773C CA 2477773 C CA2477773 C CA 2477773C CA 2477773 A CA2477773 A CA 2477773A CA 2477773 A CA2477773 A CA 2477773A CA 2477773 C CA2477773 C CA 2477773C
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- CA
- Canada
- Prior art keywords
- diclofenac
- composition according
- salt
- tromethamine
- composition
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-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Rheumatology (AREA)
- Otolaryngology (AREA)
- Oncology (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Pain & Pain Management (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
Abstract
A composition for the topical treatment of oropharyngeal cavity disorders, comprising an aqueous solution of the salt of diclofenac with tromethamine, in which the amount of the said salt is of from 0.1% to 0.2% (w/w) and the pH is adjusted between 7 and 8.
Description
"Diclofenac-based composition for the topical treatment of oropharyngeal cavity disorders"
**********
The present invention relates to a diclofenac-based composition for the topical treatment of oropharyngeal cavity disorders.
It is known that diclofenac [2-(2,6-dichloroanilino)phenylacetic acid] is a widely-used pharmaceutical product with anti-inflammatory, antipyretic and analgesic properties. It is mainly administered systemically in unmodified form or in the form of a salt thereof with mineral or organic bases.
However, its salts are virtually insoluble in water.
Example 2 of patent US-4 407 824 describes the preparation of the salt of diclofenac with tromethamine [tris(hydroxymethyl)methylamine], but does not specify its solubility in water and does not give an example of any pharmaceutical form containing the abovementioned salt.
The problem of the insolubility in water of diclofenac salts is also acknowledged in EP-A-0 521 393, which proposes to solve the said problem by means of the choline salt. This salt is described as a compound that is surprisingly soluble in water and suitable, inter alia, also for the preparation of mouthwashes.
However, the choline salt has the typical drawbacks of choline, which is well known for its unpleasant odour and taste.
These drawbacks are particularly unfavourable in the case of compositions for the topical treatment of oropharyngeal cavity disorders, for instance mouthwashes and oral sprays, which need to remain in contact with the mucosae for a relatively long period of time in order to exert their therapeutic effect.
Despite the addition of large amounts of ingredients capable of masking its taste [0.5% (w/w) of acesulfame and 35% (w/w) of sorbitolJ, compositions for the topical treatment of oropharyngeal cavity disorders based on the salt of diclofenac with choline are relatively unpalatable.
There is therefore still a great need for a diclofenac-based composition of pleasant or at the very least neutral taste, for the topical treatment of oropharyngeal cavity disorders.
Although A. Fini et al. have reported that the solubility in water of the tromethamine salt is considered to be 0.167 g in 100 ml (European J.
Pharm. Sci. 4, 231, 1996), the tests conducted by the present inventor have demonstrated that amounts of diclofenac ranging from 0.071 to 0.142 g do not dissolve in 100 ml of water even in the presence of stoichiometric amounts (from 0.029 to 0.058 g, respectively) of tromethamine (Comparative Examples 1 and 2).
Surprisingly, it has now been found that the abovementioned compositions containing from 0.071 to 0.142 g of diclofenac with stoichiometric amounts (from 0.029 to 0.058 g, respectively) of tromethamine in 100 ml of water become clear and remain so for a long time if their pH is brought to 7-8 (Examples 1 and 2).
Also surprisingly, it has been found that the palatability of these solutions is good and that it is also very easy to improve it by means of modest amounts of standard flavouring agents and sweeteners.
One subject of the present invention is thus a composition for the topical treatment of oropharyngeal cavity disorders, characterized in that it comprises an aqueous solution of the salt of diclofenac with tromethamine, in which the amount of the said salt is of from 0.1 % to 0.2% (w/w) and the pH is adjusted between 7 and 8.
The preferred concentration of the salt of diclofenac with tromethamine in the composition of the present invention is 0.1 % (w/w).
Advantageously, the abovementioned mouthwash comprises other standard ingredients, for instance ethanol, polyhydroxylated alcohols, complexing agents, preserving agents, humectants, sweeteners, flavouring agents, colouring agents and the like.
Typical examples of these ingredients are:
polyhydroxylated alcohols: glycerol, propylene glycol and polyethylene glycol;
complexing agents: sodium edetate;
preserving agents: methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, sodium benzoate;
humectants: glyceryl polyethylene glycol ricinoleate;
sweeteners: sodium saccharinate, sorbitol, acesulfame and xylitol;
gelling agents: block copolymers of polyethylene glycol and polypropylene glycol such as, for example, PoloxamerT"" 407;
flavouring agents: mint flavouring agent, natural tutti frutti flavouring agent and grenadine flavouring agent;
colouring agents: quinoline yellow E 104 and patent blue E 131.
Typical examples of oropharyngeal cavity disorders which benefit from treatment with the composition of the present invention are:
gingivitis, glossitis, stomatitis, aphthae, paradentosis, paradentitis, laryngitis, pharyngitis and mucositis caused by radiotherapy and chemotherapy. In addition, the composition of the invention is useful in the treatment of after-effects of dental and/or general surgery.
Preferred dosage forms of the composition of the present invention are mouthwashes and oral sprays.
These dosage forms can be readily prepared according to techniques known to pharmaceutical chemists, and include stages such as mixing, dissolution, sterilization and the like.
The following examples serve to illustrate the invention without, however, limiting it.
Example 1 Mouthwash A
**********
The present invention relates to a diclofenac-based composition for the topical treatment of oropharyngeal cavity disorders.
It is known that diclofenac [2-(2,6-dichloroanilino)phenylacetic acid] is a widely-used pharmaceutical product with anti-inflammatory, antipyretic and analgesic properties. It is mainly administered systemically in unmodified form or in the form of a salt thereof with mineral or organic bases.
However, its salts are virtually insoluble in water.
Example 2 of patent US-4 407 824 describes the preparation of the salt of diclofenac with tromethamine [tris(hydroxymethyl)methylamine], but does not specify its solubility in water and does not give an example of any pharmaceutical form containing the abovementioned salt.
The problem of the insolubility in water of diclofenac salts is also acknowledged in EP-A-0 521 393, which proposes to solve the said problem by means of the choline salt. This salt is described as a compound that is surprisingly soluble in water and suitable, inter alia, also for the preparation of mouthwashes.
However, the choline salt has the typical drawbacks of choline, which is well known for its unpleasant odour and taste.
These drawbacks are particularly unfavourable in the case of compositions for the topical treatment of oropharyngeal cavity disorders, for instance mouthwashes and oral sprays, which need to remain in contact with the mucosae for a relatively long period of time in order to exert their therapeutic effect.
Despite the addition of large amounts of ingredients capable of masking its taste [0.5% (w/w) of acesulfame and 35% (w/w) of sorbitolJ, compositions for the topical treatment of oropharyngeal cavity disorders based on the salt of diclofenac with choline are relatively unpalatable.
There is therefore still a great need for a diclofenac-based composition of pleasant or at the very least neutral taste, for the topical treatment of oropharyngeal cavity disorders.
Although A. Fini et al. have reported that the solubility in water of the tromethamine salt is considered to be 0.167 g in 100 ml (European J.
Pharm. Sci. 4, 231, 1996), the tests conducted by the present inventor have demonstrated that amounts of diclofenac ranging from 0.071 to 0.142 g do not dissolve in 100 ml of water even in the presence of stoichiometric amounts (from 0.029 to 0.058 g, respectively) of tromethamine (Comparative Examples 1 and 2).
Surprisingly, it has now been found that the abovementioned compositions containing from 0.071 to 0.142 g of diclofenac with stoichiometric amounts (from 0.029 to 0.058 g, respectively) of tromethamine in 100 ml of water become clear and remain so for a long time if their pH is brought to 7-8 (Examples 1 and 2).
Also surprisingly, it has been found that the palatability of these solutions is good and that it is also very easy to improve it by means of modest amounts of standard flavouring agents and sweeteners.
One subject of the present invention is thus a composition for the topical treatment of oropharyngeal cavity disorders, characterized in that it comprises an aqueous solution of the salt of diclofenac with tromethamine, in which the amount of the said salt is of from 0.1 % to 0.2% (w/w) and the pH is adjusted between 7 and 8.
The preferred concentration of the salt of diclofenac with tromethamine in the composition of the present invention is 0.1 % (w/w).
Advantageously, the abovementioned mouthwash comprises other standard ingredients, for instance ethanol, polyhydroxylated alcohols, complexing agents, preserving agents, humectants, sweeteners, flavouring agents, colouring agents and the like.
Typical examples of these ingredients are:
polyhydroxylated alcohols: glycerol, propylene glycol and polyethylene glycol;
complexing agents: sodium edetate;
preserving agents: methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, sodium benzoate;
humectants: glyceryl polyethylene glycol ricinoleate;
sweeteners: sodium saccharinate, sorbitol, acesulfame and xylitol;
gelling agents: block copolymers of polyethylene glycol and polypropylene glycol such as, for example, PoloxamerT"" 407;
flavouring agents: mint flavouring agent, natural tutti frutti flavouring agent and grenadine flavouring agent;
colouring agents: quinoline yellow E 104 and patent blue E 131.
Typical examples of oropharyngeal cavity disorders which benefit from treatment with the composition of the present invention are:
gingivitis, glossitis, stomatitis, aphthae, paradentosis, paradentitis, laryngitis, pharyngitis and mucositis caused by radiotherapy and chemotherapy. In addition, the composition of the invention is useful in the treatment of after-effects of dental and/or general surgery.
Preferred dosage forms of the composition of the present invention are mouthwashes and oral sprays.
These dosage forms can be readily prepared according to techniques known to pharmaceutical chemists, and include stages such as mixing, dissolution, sterilization and the like.
The following examples serve to illustrate the invention without, however, limiting it.
Example 1 Mouthwash A
100 g of Mouthwash A contains:
salt of diclofenac with tromethamine~ 0.104 g xylitol 10.000 g PoloxamerT"" 407 0.500 g sodium benzoate 0.500 g natural mint flavouring agent 0.500 ml aqueous solution of E 131 (1 mg/ml) 0.200 ml pH 7.8 phosphate buffer~~ qs 100 g pH 7.6 1 equal to 0.074 g of acidic diclofenac ..
one litre of solution in purified water contains: anhydrous dibasic sodium phosphate (5.803 g), anhydrous monobasic potassium phosphate (3.522 g) and 1 N sodium hydroxide (18.70 ml).
Example 2 Mouthwash B
100 g of Mouthwash B have the same composition as Mouthwash A
except that:
- it also contains natural tutti frutti flavouring agent (0.04 ml) and natural grenadine flavouring agent (0.02 ml), and - in place of 0.2 ml of aqueous solution of E 131 (1 mg/ml), it contains 0.25 ml of aqueous solution of E 124 (10 mg/ml).
Comparative Example 1 Mouthwash C
A mouthwash was prepared having the same composition as Mouthwash A, except that it contained purified water in place of the pH
7.8 phosphate buffer.
Comparative Example 2 Mouthwash D
salt of diclofenac with tromethamine~ 0.104 g xylitol 10.000 g PoloxamerT"" 407 0.500 g sodium benzoate 0.500 g natural mint flavouring agent 0.500 ml aqueous solution of E 131 (1 mg/ml) 0.200 ml pH 7.8 phosphate buffer~~ qs 100 g pH 7.6 1 equal to 0.074 g of acidic diclofenac ..
one litre of solution in purified water contains: anhydrous dibasic sodium phosphate (5.803 g), anhydrous monobasic potassium phosphate (3.522 g) and 1 N sodium hydroxide (18.70 ml).
Example 2 Mouthwash B
100 g of Mouthwash B have the same composition as Mouthwash A
except that:
- it also contains natural tutti frutti flavouring agent (0.04 ml) and natural grenadine flavouring agent (0.02 ml), and - in place of 0.2 ml of aqueous solution of E 131 (1 mg/ml), it contains 0.25 ml of aqueous solution of E 124 (10 mg/ml).
Comparative Example 1 Mouthwash C
A mouthwash was prepared having the same composition as Mouthwash A, except that it contained purified water in place of the pH
7.8 phosphate buffer.
Comparative Example 2 Mouthwash D
A mouthwash was prepared having the same composition as Mouthwash B, except that it contained purified water in place of the pH 7.8 phosphate buffer.
Stability Mouthwashes A and B were found to be stable.
In contrast, Mouthwashes C and D released over time, especially under cold conditions, a precipitate of diclofenac.
This behaviour was entirely unexpected as regards the mouthwashes containing an amount of salt of diclofenac with tromethamine that is less than the solubility limit reported by Fini et al. (cited above).
Stability Mouthwashes A and B were found to be stable.
In contrast, Mouthwashes C and D released over time, especially under cold conditions, a precipitate of diclofenac.
This behaviour was entirely unexpected as regards the mouthwashes containing an amount of salt of diclofenac with tromethamine that is less than the solubility limit reported by Fini et al. (cited above).
Claims (8)
1. Composition for the topical treatment of oropharyngeal cavity disorders, characterized in that it comprises an aqueous solution of the salt of diclofenac with tromethamine, in which the amount of the said salt is of from 0.1 % to 0.2% (w/w) and the pH is adjusted between 7 and 8.
2. Composition according to Claim 1, characterized in that it contains 0.10% (w/w) of the salt of diclofenac with tromethamine.
3. Composition according to Claim 1 or 2, characterized in that it further comprises a sweetener selected from the group comprising sodium saccharinate, sorbitol, acesulfame and xylitol.
4. Composition according to any one of the preceding Claims 1 to 3, characterized in that it further comprises a preserving agent selected from the group comprising sodium benzoate, methyl p-hydroxybenzoate and propyl p-hydroxybenzoate.
5. Composition according to any one of the preceding Claims 1 to 4, characterized in that it further comprises a gelling agent consisting of a block copolymer of polyethylene glycol and polypropylene glycol.
6. Composition according to any one of the preceding Claims 1 to 5, characterized in that it further comprises a pharmaceutically acceptable flavouring agent.
7. Composition according to any one of the preceding Claims 1 to 6, characterized in that it further comprises a pharmaceutically acceptable colouring agent.
8. Composition according to any one of the preceding Claims 1 to 7, characterized in that it is used in the treatment of gingivitis, glossitis, stomatitis, aphthae, paradentosis, paradentitis, laryngitis, pharyngitis, mucositis of the oral cavity caused by radiotherapy and chemotherapy, and of after-effects of dental and/or general surgery.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI2002A000986 | 2002-05-10 | ||
| IT2002MI000986A ITMI20020986A1 (en) | 2002-05-10 | 2002-05-10 | COMPOSITION BASED ON DICLOFENAC FOR THE TOPICAL TREATMENT OF AFFECTIONS OF THE OROPHARINGOUS CABLE |
| PCT/EP2003/004044 WO2003094905A1 (en) | 2002-05-10 | 2003-04-16 | Diclofenac-based composition for the topical treatment of oropharyngeal cavity disorders |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2477773A1 CA2477773A1 (en) | 2003-11-20 |
| CA2477773C true CA2477773C (en) | 2011-01-18 |
Family
ID=11449862
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2477773A Expired - Fee Related CA2477773C (en) | 2002-05-10 | 2003-04-16 | A stable diclofenac-tromethamine composition for the topical treatment of oropharyngeal cavity disorders |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US20050100597A1 (en) |
| EP (1) | EP1503747B1 (en) |
| JP (1) | JP2005526120A (en) |
| KR (1) | KR20040111415A (en) |
| CN (1) | CN1303992C (en) |
| AR (1) | AR039977A1 (en) |
| AT (1) | ATE333872T1 (en) |
| AU (1) | AU2003232480B2 (en) |
| CA (1) | CA2477773C (en) |
| DE (1) | DE60307086T2 (en) |
| DK (1) | DK1503747T3 (en) |
| EA (1) | EA006165B1 (en) |
| ES (1) | ES2268402T3 (en) |
| GE (1) | GEP20063822B (en) |
| HK (1) | HK1071312A1 (en) |
| IL (2) | IL163871A0 (en) |
| IT (1) | ITMI20020986A1 (en) |
| MX (1) | MXPA04010401A (en) |
| PL (1) | PL215221B1 (en) |
| PT (1) | PT1503747E (en) |
| UA (1) | UA79110C2 (en) |
| WO (1) | WO2003094905A1 (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20032523A1 (en) * | 2003-12-19 | 2005-06-20 | Acraf | DOSAGE FORM FOR ORAL USE INCLUDING A DRUG |
| ITMI20040235A1 (en) * | 2004-02-13 | 2004-05-13 | Therapicon Srl | PHARMACEUTICAL PREPARATION FOR THE ORAL CABLE |
| CN101138544B (en) * | 2006-09-06 | 2010-09-29 | 上海医药工业研究院 | Diclofenac or the salt partial film forming gel composition and uses thereof |
| AU2007311019B2 (en) | 2006-10-17 | 2013-05-16 | Nuvo Pharmaceuticals, Inc | Diclofenac gel |
| US8546450B1 (en) | 2009-03-31 | 2013-10-01 | Nuvo Research Inc. | Treatment of pain with topical diclofenac compounds |
| US8618164B2 (en) | 2009-03-31 | 2013-12-31 | Nuvo Research Inc. | Treatment of pain with topical diclofenac compounds |
| US20120003162A1 (en) * | 2010-06-30 | 2012-01-05 | Mcneil-Ppc, Inc. | Methods of Preparing Non-Alcohol Bioactive Esential Oil Mouth Rinses |
| KR101936192B1 (en) | 2010-12-29 | 2019-01-08 | 엘지전자 주식회사 | Outdoor unit for air conditioner |
| DE102011111944A1 (en) * | 2011-08-29 | 2013-02-28 | Richard A. Huthmacher | Use of diclofenac for the prevention and treatment of influenza infections as well as disease symptoms caused by influenza infections |
| JP2017526638A (en) * | 2014-06-30 | 2017-09-14 | ミトコンドリアル サブストレート インベンション リミテッドＭｉｔｏｃｈｏｎｄｒｉａｌ Ｓｕｂｓｔｒａｔｅ Ｉｎｖｅｎｔｉｏｎ Ｌｉｍｉｔｅｄ | Nutrient solutions for improving cognitive function |
| CN104546527A (en) * | 2014-12-29 | 2015-04-29 | 福建省闽东力捷迅药业有限公司 | Collutory containing sodium aescinate and preparation method of collutory |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT370721B (en) * | 1981-02-24 | 1983-04-25 | Ciba Geigy Ag | METHOD FOR PRODUCING NEW SALTS OF 2- (2,6-DICHLORANILINO) -PHENYLACETIC ACID, THE |
| ES2054089T3 (en) * | 1988-11-10 | 1994-08-01 | Ciba Geigy Ag | LIQUID ORAL FORMULATIONS. |
| CA1340994C (en) * | 1989-09-21 | 2000-05-16 | Rudolf Edgar Dr. Falk | Treatment of conditions and disease |
| US5028413A (en) * | 1990-03-21 | 1991-07-02 | Bausch & Lomb Incorporated | Novel fluoride-containing dentifrice |
| IT1243342B (en) * | 1990-07-13 | 1994-06-10 | Farcon Ag | ORAL PHARMACEUTICAL COMPOSITIONS FOR LIQUID ANTI-INFLAMMATORY ACTIVITIES |
| US5972906A (en) * | 1991-07-03 | 1999-10-26 | Hyal Pharmaceutical Corporation | Treatment of mucous membrane disease, trauma or condition and for the relief of pain thereof |
| IT1250636B (en) * | 1991-07-04 | 1995-04-21 | Ricerche Di Schiena Del Dr Mic | SALT OF DICLOFENAC, METHOD OF PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT. |
| US5626838A (en) * | 1995-03-13 | 1997-05-06 | The Procter & Gamble Company | Use of ketorolac for treatment of squamous cell carcinomas of the oral cavity or oropharynx |
| CN1059797C (en) * | 1995-11-22 | 2000-12-27 | 王树力 | Spray containing diclofenac sodium |
-
2002
- 2002-05-10 IT IT2002MI000986A patent/ITMI20020986A1/en unknown
-
2003
- 2003-04-16 IL IL16387103A patent/IL163871A0/en active IP Right Grant
- 2003-04-16 CN CNB038105764A patent/CN1303992C/en not_active Expired - Fee Related
- 2003-04-16 WO PCT/EP2003/004044 patent/WO2003094905A1/en active IP Right Grant
- 2003-04-16 PL PL371426A patent/PL215221B1/en unknown
- 2003-04-16 AU AU2003232480A patent/AU2003232480B2/en not_active Ceased
- 2003-04-16 CA CA2477773A patent/CA2477773C/en not_active Expired - Fee Related
- 2003-04-16 US US10/505,178 patent/US20050100597A1/en not_active Abandoned
- 2003-04-16 ES ES03749856T patent/ES2268402T3/en not_active Expired - Lifetime
- 2003-04-16 MX MXPA04010401A patent/MXPA04010401A/en unknown
- 2003-04-16 DE DE60307086T patent/DE60307086T2/en not_active Expired - Lifetime
- 2003-04-16 UA UA20040907893A patent/UA79110C2/en unknown
- 2003-04-16 KR KR10-2004-7014564A patent/KR20040111415A/en active IP Right Grant
- 2003-04-16 JP JP2004502991A patent/JP2005526120A/en active Pending
- 2003-04-16 DK DK03749856T patent/DK1503747T3/en active
- 2003-04-16 AT AT03749856T patent/ATE333872T1/en active
- 2003-04-16 EA EA200401090A patent/EA006165B1/en not_active IP Right Cessation
- 2003-04-16 PT PT03749856T patent/PT1503747E/en unknown
- 2003-04-16 GE GE5669A patent/GEP20063822B/en unknown
- 2003-04-16 EP EP03749856A patent/EP1503747B1/en not_active Expired - Lifetime
- 2003-05-08 AR ARP030101608A patent/AR039977A1/en not_active Application Discontinuation
-
2004
- 2004-09-01 IL IL163871A patent/IL163871A/en unknown
-
2005
- 2005-05-24 HK HK05104340A patent/HK1071312A1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003094905A8 (en) | 2004-04-01 |
| MXPA04010401A (en) | 2005-02-17 |
| CN1652763A (en) | 2005-08-10 |
| IL163871A (en) | 2007-10-31 |
| ITMI20020986A0 (en) | 2002-05-10 |
| CN1303992C (en) | 2007-03-14 |
| AU2003232480B2 (en) | 2008-07-31 |
| PT1503747E (en) | 2006-11-30 |
| AU2003232480A1 (en) | 2003-11-11 |
| DE60307086D1 (en) | 2006-09-07 |
| KR20040111415A (en) | 2004-12-31 |
| JP2005526120A (en) | 2005-09-02 |
| EA006165B1 (en) | 2005-10-27 |
| EA200401090A1 (en) | 2005-02-24 |
| PL215221B1 (en) | 2013-11-29 |
| US20050100597A1 (en) | 2005-05-12 |
| ITMI20020986A1 (en) | 2003-11-10 |
| DK1503747T3 (en) | 2006-11-27 |
| CA2477773A1 (en) | 2003-11-20 |
| GEP20063822B (en) | 2006-05-10 |
| IL163871A0 (en) | 2005-12-18 |
| PL371426A1 (en) | 2005-06-13 |
| ATE333872T1 (en) | 2006-08-15 |
| WO2003094905A1 (en) | 2003-11-20 |
| DE60307086T2 (en) | 2007-02-01 |
| UA79110C2 (en) | 2007-05-25 |
| AR039977A1 (en) | 2005-03-09 |
| EP1503747B1 (en) | 2006-07-26 |
| ES2268402T3 (en) | 2007-03-16 |
| HK1071312A1 (en) | 2005-07-15 |
| EP1503747A1 (en) | 2005-02-09 |
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